This invention is directed towards xcex94-lactone compounds and analogs thereof such as lactams, and in particular to xcex3-phenyl-substituted xcex94-lactone and analogs thereof, and therapeutic uses related thereto.
The Inflammatory Response (Inflammation)
Inflammation is an essential localized host response to invading microorganisms or tissue injury which involves cells of the immune system. The classic signs of inflammation include redness (erythema), swelling (edema), pain and increased heat production (pyrema) at the site of injury. The inflammatory response allows the body to specifically recognize and eliminate an invading organism and/or repair tissue injury. Many of the acute changes at the site of inflammation are either directly or indirectly attributable to the massive influx of leukocytes (e.g., neutrophils, eosinophils, lymphocytes, monocytes) which is intrinsic to this response. Leukocytic infiltration and accumulation in tissue results in their activation and subsequent release of inflammatory mediators such as LTB4, prostaglandins, TNF-xcex1, IL-1xcex2, IL-8, IL-5, IL-6, histamine, proteases and reactive oxygen species for example.
Normal inflammation is a highly regulated process that is tightly controlled at several levels for each of the cell types involved in the response. For example, expression of the pro-inflammatory cytokine TNF-xcex1 is controlled at the level of gene expression, translation, post-translational modification and release of the mature form from the cell membrane. Many of the proteins up-regulated during inflammation are controlled by the transcription factor, NF-xcexaB. Pro-inflammatory responses are normally countered by endogenous anti-inflammatory mechanisms such as generation of IL-10 or IL-4. A characteristic of a normal inflammatory response is that it is temporary in nature and is followed by a resolution phase which brings the state of the tissue back to its prior condition. The resolution phase is thought to involve up-regulation of anti-inflammatory mechanisms, such as IL-10, as well as down-regulation of the pro-inflammatory processes.
Inflammatory Disease
Inflammatory disease occurs when an inflammatory response is initiated that is inappropriate and/or does not resolve in the normal manner but rather persists and results in a chronic inflammatory state. Inflammatory disease may be systemic (e.g. lupus) or localized to particular tissues or organs and exerts an enormous personal and economic burden on society. Examples of some of the most common and problematic inflammatory diseases are rheumatoid arthritis, inflammatory bowel disease, psoriasis, asthma, emphysema, colitis and ischemia-reperfusion injury.
A common underlying theme in inflammatory disease is a perturbation of the cellular immune response that results in recognition of host proteins (antigens) as foreign. Thus the inflammatory response becomes misdirected at host tissues with effector cells targeting specific organs or tissues often resulting in irreversible damage. The self-recognition aspect of auto-immune disease is often reflected by the clonal expansion of T-cell subsets characterized by a particular T-cell receptor (TCR) subtype in the disease state. Often inflammatory disease is also characterized by an imbalance in the levels of T-helper (Th) subsets (i.e., Th1 cells vs. Th2 cells).
Therapeutic strategies aimed at curing inflammatory diseases usually fall into one of two categories: (a) down-modulation of processes that are up-regulated in the disease state or (b) up-regulation of anti-inflammatory pathways in the affected cells or tissues. Most regimes currently employed in the clinic fall into the first category. Some examples of which are corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs).
Many of the tissue, cellular and biochemical processes which are perturbed in inflammatory disease have been elucidated and this has allowed the development of experimental models or assays to mimic the disease state. These in-vitro assays enable selection and screening of compounds with a high probability of therapeutic efficacy in the relevant inflammatory disease. Thus, currently employed assays used to model the importance of the activated leukocytes in the development of acute inflammation and maintenance of the chronic inflammatory state are assays monitoring leukocyte chemotaxis and cellular degranulation and cytokine synthesis and reactive oxygen species (ROS) production assays in vitro. Since a result of acute or chronic neutrophil activation is release of ROS with resultant tissue damage, an assay for scavengers of ROS allows detection of compounds with potential therapeutic efficacy. Cellular assays to detect inhibitors of TNF-xcex1 release from stimulated macrophage or monocytic cells are an important component of an in vitro model for inflammation as this cytokine is upregulated and has been shown to contribute to the pathology in many inflammatory diseases. Since elevated cAMP in affected cells has been shown to modulate or dampen the inflammatory response, monitoring cellular cyclic AMP (cAMP) levels, and the activity of pathways controlling cAMP levels allows for the detection of potential anti-inflammatory compounds. Assays may include monitoring the level of cAMP itself, phosphodiesterase activity, or changes in cAMP response element (CRE)-luciferase activity.
Rheumatoid Arthritis
Rheumatoid arthritis (RA), the most common form of inflammatory arthritis, is an auto-immune disorder of unknown etiology which affects 1% of the adult population and is characterized by symmetric, chronic, erosive synovitis (inflammation of the joint synovial lining) and frequent multisystem involvement. Interestingly, it is 3-6 times more prevalent in women than men. Most patients exhibit a chronic fluctuating course of disease that, if left untreated, results in progressive joint destruction, deformity, disability, and premature death. Symptoms indicative of RA include pain and swelling of the joints (usually symmetrical), morning stiffness of joints and muscles, general weakness/fatigue and fever and weight loss. RA results in more than 9 million physician visits and more than 250,000 hospitalizations per year in the U.S. each year. It frequently affects patients in their most productive years, and thus, disability results in major economic loss.
Recent insights have established that the genetic background, especially the structure of the class II major histocompatibilty (MHC) genes, plays a critical role in an individual""s susceptibility and the severity of the disease. The current understanding of cytokine networks, chemokines, growth factors and adhesion molecules have led to the appreciation that T cell-dependent and T cell-independent pathways contribute to the initiation and perpetuation of rheumatoid arthritis. Furthermore, much has been learned about the specific cellular and biochemical events responsible for the bone and cartilage destruction that characterizes this disorder. At the tissue level, RA is characterized by synovial hyperplasia, hypertrophy, angiogenesis and attachment and invasion of synovial fibroblasts into adjacent cartilage and bone. In active RA there are increased levels of the pro-inflammatory cytokines TNF-xcex1, IL-1 and IL-6 relative to the anti-inflammatory cytokines in affected joints.
Current Treatments for Rheumatoid Arthritis and Other Inflammatory Diseases
At present there is no cure or prevention (prophylactic) available for rheumatoid arthritis, only regimes that address symptoms such as pain and stiffness. The five major treatment modalities for this disease include medication (pharmacological), physical (exercise), joint protection and lifestyle changes and surgery.
Therapeutics for rheumatoid arthritis can be divided into three groups: nonsteroidal anti-inflammatory drugs (NSAIDs), disease modifying anti-rheumatic drugs (DMARDs) also known as second line agents and corticosteroids.
NSAIDs reduce pain at low doses and relieve some of the inflammatory symptoms (swelling and stiffness) at higher doses through inhibition of prostaglandin synthesis. Examples of non-prescription NSAIDs include acetylsalicylic acid (ASA(copyright), Aspirin(copyright), Anacin(copyright), etc.) and ibuprofen (Motrin(copyright), Advil(copyright), etc.). Examples of NSAIDs requiring a prescription include Naprosyn(copyright), Relafen(copyright), Indocid(copyright), Voltaren(copyright), Feldene(copyright) and Clinoril(copyright). Although these medications effectively address the acute inflammatory component of rheumatoid arthritis, they only treat the symptoms of and do not change the progression of the underlying disease. The deleterious side effects of NSAIDs can be serious with prolonged administration and are mainly gastrointestinal (heartburn, bleeding or ulcers).
DMARDs are often prescribed if inflammation persists for more than 6 weeks or when the arthritis affects many joints simultaneously. They are usually administered in addition to a NSAID or steroid. Many DMARDs work by suppressing immune cells involved in the inflammatory response thus slowing progression of the disease. However, they are unable to reverse permanent joint damage. The most common drugs of this class are gold salts, methotrexate, azathioprine, sulphasalazine, hydroxychloroquine, penicillamine and chloroquine. DMARDs often take several weeks for beneficial effects to be seen and in many cases the exact mode of efficacy in rheumatoid arthritis is unknown. Side effects are numerous including mouth sores, rashes, diarrhea and nausea. More serious side effects which necessitate careful monitoring through regular blood and urine tests include liver and kidney damage, excessive lowering of the white blood cell count (immune suppression) and platelet count (blood clotting).
Corticosteroids are frequently prescribed in RA patients with extreme inflammation accompanied by severe pain, swelling and stiffness in the joints. They are also used to treat systemic rheumatoid arthritis which can affect the lining of the lungs and blood vessels. The route of administration is usually oral (i.e., prednisone) but the drug can also be injected directly into the affected joint, vein, muscle or alternative site of inflammation. Side effects from long-term use of steroids in rheumatoid arthritis are serious and include cataracts, high blood pressure, muscle wasting, bruising, thinning of skin and bones, weight gain, diabetes and susceptibility to infection.
Even though only 5% of patients diagnosed with rheumatoid arthritis will go on to develop more severe disease (involving debilitating and irreversible joint damage) those that do certainly do not have an ideal set of therapeutics available to satisfactorily manage and/or cure the disease. The currently available NSAIDs (even selective COX-2 inhibitors) can successfully ameliorate the acute symptoms of rheumatoid arthritis such as swelling, pain and joint stiffness. However they do not affect either progression of joint destruction or effect any reversal of articular or bone erosion. Second line drugs such as DMARD""s or corticosteroids may temporarily slow progression of the disease and reduce symptoms, but usually suffer from an unacceptable side-effect profile or variable patient response and cannot reverse existing joint damage. There is a significant need for therapeutic agents that effectively arrest or reverse disease progression in rheumatoid arthritis.
In one aspect, the present invention provides a composition comprising a compound according to formula (1) and salts, solvates, isolated stereoisomers, and mixtures thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, 
wherein each of hydrogens Ha, Hb, Hc, Hd, He, Hf and Hg may independently be replaced with a group selected from xe2x80x94W and xe2x80x94R7(W)n, and M1 represents xe2x80x94W or xe2x80x94R7(W)n, wherein
W is selected from xe2x80x94NH2, xe2x80x94CONH2, xe2x80x94COOH, xe2x80x94CN, xe2x80x94CHO, xe2x80x94OCHO, xe2x80x94X, xe2x80x94OH, xe2x80x94NO2, xe2x80x94SH, xe2x80x94COX, xe2x80x94NHR8, xe2x80x94NR8R8, xe2x80x94CONHR8, xe2x80x94CONR8R8, xe2x80x94COOR8, xe2x80x94COR8, xe2x80x94OCOR8, xe2x80x94OR8, xe2x80x94BH2, xe2x80x94BHR8, xe2x80x94BR8R8, xe2x80x94BO2H2, xe2x80x94BO2R8R8, xe2x80x94PH2, xe2x80x94PHR8, xe2x80x94PR8R8, xe2x80x94POR8, xe2x80x94PO2R8, xe2x80x94PO3R8, xe2x80x94SR8; xe2x80x94SOR8, xe2x80x94SO2R8, xe2x80x94SONH2, xe2x80x94SONHR8, xe2x80x94SONR8R8, xe2x80x94SO2NH2, xe2x80x94SO2NHR8 and xe2x80x94SO2NR8R8;
R7 is a C1-C30 hydrocarbyl, halocarbyl or hydrohalocarbyl group wherein n of the hydrogen or halogen atoms of R7 are substituted by an equal number of W groups independently selected at each location;
R8 is a C1-C30 hydrocarbyl, halocarbyl or hydrohalocarbyl group;
n is selected from 0, 1, 2, 3, 4 and 5; and
X is selected from xe2x80x94Br, xe2x80x94Cl, xe2x80x94F, xe2x80x94I.
In other aspects of the composition comprising a compound of formula (1): Ha and Hb are hydrogen; Ha is hydrogen and Hb is xe2x80x94W; Ha is hydrogen, Hb is xe2x80x94W and the carbon to which Hb is bound has an S configuration; Ha is hydrogen, Hb is xe2x80x94W, and the carbon to which Hb is bound has an R configuration; Ha is hydrogen and Hb is xe2x80x94R7(W)n; Ha is hydrogen, Hb is xe2x80x94R7(W)n, and the carbon to which Hb is bound has an S configuration; Ha is hydrogen, Hb is xe2x80x94R7(W)n, and the carbon to which Hb is bound has an R configuration; Ha is hydrogen, Hb is xe2x80x94R7(W)n, Hb is xe2x80x94CH2-phenyl, and phenyl has 0, 1 or 2 W substitutions; HC is W; Hd and He are both hydrogen; Hf is W; Hf is selected from xe2x80x94OH and xe2x80x94OR8; Hf is selected from methoxy, ethoxy, propoxy, cyclopentyloxy, cyclohexyloxy, and benzyloxy; Hf is selected from xe2x80x94NH2, xe2x80x94NHR8, and xe2x80x94NR8R8; Hg is xe2x80x94R7(W)n; M1 is xe2x80x94W; M1 is selected from methoxy, ethoxy, propoxy, cyclopentyloxy, cyclohexyloxy, and benzyloxy; M1 is selected from xe2x80x94NH2, xe2x80x94NHR8, and xe2x80x94NR8R8; M1 is selected from xe2x80x94OH and xe2x80x94OR8; and/or M1 is xe2x80x94R7(W)n. In one embodiment, none of Ha, Hb, Hc, Hd, He, Hf or Hg is a heterocyclic ring.
The compound of formula (1) may have the stereochemistry of formula (1a) 
The compound of formula (1) may have the stereochemistry of formula (1b) 
A reference herein to compounds of formula (1) includes compounds of formulae (1a) and (1b).
In another aspect, the present invention provides a composition comprising a compound according to formula (2) and salts, solvates, isolated stereoisomers, and mixtures thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, 
wherein each of hydrogens Ha, Hb, Hc, Hd, He, Hf and Hg may independently be replaced with a group selected from xe2x80x94W and xe2x80x94R7(W)n, and M2 represents xe2x80x94W, wherein
W is selected from xe2x80x94NH2, xe2x80x94CONH2, xe2x80x94COOH, xe2x80x94CN, xe2x80x94CHO, xe2x80x94OCHO, xe2x80x94X, xe2x80x94OH, xe2x80x94NO2, xe2x80x94SH, xe2x80x94COX, xe2x80x94NHR8, xe2x80x94NR8R8, xe2x80x94CONHR8, xe2x80x94CONR8R8, xe2x80x94COOR8, xe2x80x94COR8, xe2x80x94OCOR8, xe2x80x94OR8, xe2x80x94BH2, xe2x80x94BHR8, xe2x80x94BR8R8, xe2x80x94BO2H2, xe2x80x94BO2R8R8, xe2x80x94PH2, xe2x80x94PHR8, xe2x80x94PR8R8, xe2x80x94POR8, xe2x80x94PO2R8, xe2x80x94PO3R8, xe2x80x94SR8; xe2x80x94SOR8, xe2x80x94SO2R8, xe2x80x94SONH2, xe2x80x94SONH8, xe2x80x94SONR8R8, xe2x80x94SO2NH2, xe2x80x94SO2NHR8 and xe2x80x94SO2NR8R8;
R7 is a C1-C30 hydrocarbyl, halocarbyl or hydrohalocarbyl group wherein n of the hydrogen or halogen atoms of R7 are substituted by an equal number of W groups independently selected at each location;
R8 is a C1-C30 hydrocarbyl, halocarbyl or hydrohalocarbyl group;
n is selected from 0, 1, 2, 3, 4 and 5; and
X is selected from xe2x80x94Br, xe2x80x94Cl, xe2x80x94F, xe2x80x94I.
In other aspects of compositions comprising a compound of formula (2): Ha and Hb are hydrogen; Ha is hydrogen and Hb is xe2x80x94W; Ha is hydrogen, Hb is xe2x80x94W, and the carbon to which Hb is bound has an S configuration; Ha is hydrogen, Hb is xe2x80x94W, and the carbon to which Hb is bound has an R configuration; Ha is hydrogen and Hb is xe2x80x94R7(W)n; Ha is hydrogen, Hb is xe2x80x94R7(W)n, and the carbon to which Hb is bound has an S configuration; Ha is hydrogen, Hb is xe2x80x94R7(W)n, and the carbon to which Hb is bound has an r configuration; Ha is hydrogen, and Hb is xe2x80x94CH2-phenyl, where phenyl has 0, 1 or 2 W substitutions; Hc is W; Hd and He are both hydrogen; Hf is hydrogen and Hg is W; Hg is selected from xe2x80x94OH and xe2x80x94OR8; Hg is selected from methoxy, ethoxy, propoxy, cyclopentyloxy, cyclohexyloxy, and benzyloxy; Hg is selected from xe2x80x94NH2, xe2x80x94NHR8, and xe2x80x94NR8R8; Hf is hydrogen and Hg is xe2x80x94R7(W)n; M2 is selected from xe2x80x94NH2, xe2x80x94CONH2, xe2x80x94COOH, xe2x80x94CN, xe2x80x94CHO, xe2x80x94OCHO, xe2x80x94X, xe2x80x94OH, xe2x80x94NO2, xe2x80x94SH, xe2x80x94COX, xe2x80x94NHR8, xe2x80x94NR8R8, xe2x80x94CONHR8, xe2x80x94CONR8R8, xe2x80x94COOR8, xe2x80x94COR8, xe2x80x94OCOR8, and xe2x80x94OR8; and/or M2 is selected from xe2x80x94NH2, xe2x80x94NHR8, xe2x80x94NR8R8, xe2x80x94OH, and xe2x80x94OR8. In a preferred embodiment, none of Ha, Hb, Hc, Hd, He, Hf or Hg may be replaced with a heterocyclic ring system.
The compound of formula (2) may have the stereochemistry of formula (2a) 
The compound of formula (2) may have the stereochemistry of formula (2b) 
A reference herein to compounds of formula (2) includes reference to compounds of formulae (2a) and (2b).
In another aspect, the present invention provides a compound according to formula (3) and salts, solvates, isolated stereoisomers, and mixtures thereof, 
wherein each of hydrogens Ha, Hc, Hd, He, Hf and Hg may independently be replaced with a group selected from xe2x80x94W and xe2x80x94R7(W)n, and Hb may be replaced with xe2x80x94W, wherein
W is selected from xe2x80x94NH2, xe2x80x94CONH2, xe2x80x94COOH, xe2x80x94CN, xe2x80x94CHO, xe2x80x94OCHO, xe2x80x94X, xe2x80x94OH, xe2x80x94NO2, xe2x80x94SH, xe2x80x94COX, xe2x80x94NHR8, xe2x80x94NR8R8, xe2x80x94CONHR8, xe2x80x94CONR8R8, xe2x80x94COOR8, xe2x80x94COR8, xe2x80x94OCOR8, xe2x80x94OR8, xe2x80x94BH2, xe2x80x94BHR8, xe2x80x94BR8R8, xe2x80x94BO2H2, xe2x80x94BO2R8R8, xe2x80x94PH2, xe2x80x94PHR8, xe2x80x94PR8R8, xe2x80x94POR8, xe2x80x94PO2R8, xe2x80x94PO3R8, xe2x80x94SR8; xe2x80x94SOR8, xe2x80x94SO2R8, xe2x80x94SONH2, xe2x80x94SONHR8, xe2x80x94SONR8R8, xe2x80x94SO2NH2, xe2x80x94SO2NHR8 and xe2x80x94SO2NR8R8;
R7 is a C1-C30 hydrocarbyl, halocarbyl or hydrohalocarbyl group wherein n of the hydrogen or halogen atoms of R7 are substituted by an equal number of W groups independently selected at each location;
R8 is a C1-C30 hydrocarbyl, halocarbyl or hydrohalocarbyl group;
n is selected from 0, 1, 2, 3, 4 and 5; and
X is selected from xe2x80x94Br, xe2x80x94Cl, xe2x80x94F, xe2x80x94I.
In a preferred embodiment, at least two of He, Hf, and Hg are not hydrogen. In another preferred embodiment, Hg is not R7(W)n. In another preferred embodiment, Hg is neither hydrogen nor R7(W)n. In another preferred embodiment, none of Ha, Hb, Hc, Hd, He, Hf or Hg is a heterocyclic ring.
In other aspects, in the compound of formula (3): Ha is hydrogen; Ha is not hydrogen, and the carbon to which Ha is bound has an S configuration; Ha is not hydrogen and the carbon to which Ha is bound has an R configuration; Ha is xe2x80x94W; Ha is xe2x80x94R7(W)n; Ha is xe2x80x94CH2-phenyl, and phenyl has 0, 1 or 2 W substitutions; Hb is W; Hb is xe2x80x94CN; Hc and Hd are both hydrogen; He is hydrogen; He is hydrogen and Hf is W; He is hydrogen and Hf is selected from xe2x80x94OH and xe2x80x94OR8; He is hydrogen and Hf is selected from methoxy, ethoxy, propoxy, cyclopentyloxy, cyclohexyloxy, and benzyloxy; He is hydrogen and Hf is selected from xe2x80x94NH2, xe2x80x94NHR8, and xe2x80x94NR8R8; Hg is hydrogen; Hg is xe2x80x94W; Hg is selected from xe2x80x94OH and xe2x80x94OR8; Hg is selected from methoxy, ethoxy, propoxy, cyclopentyloxy, cyclohexyloxy, and benzyloxy; wherein Hg is selected from xe2x80x94NH2, xe2x80x94NHR8, and xe2x80x94NR8R8; Hg is xe2x80x94R7(W)n; and/or Hg is C1-C30alkyl and n=0.
The compound of formula (3) may have the stereochemistry of formula (3a) 
The compound of formula (3) may have the stereochemistry of formula (3b) 
A reference herein to compounds of formula (3) includes reference to compounds of formulae (3a) and (3b).
In another aspect, the present invention provides compounds of formula (4) 
wherein, Q represents a multivalent atom other than carbon; and
each of the carbons at positions 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, and 19 in formula (4), as well as Q to the extent that it may be substituted, is independently substituted at each occurrence with H, xe2x80x94W or xe2x80x94R7(W)n, wherein
W is selected from xe2x80x94NH2, xe2x80x94CONH2, xe2x80x94COOH, xe2x80x94CN, xe2x80x94CHO, xe2x80x94OCHO, xe2x80x94X, xe2x80x94OH, xe2x80x94NO2, xe2x80x94SH, xe2x80x94COX, xe2x80x94NHR8, xe2x80x94NR8R8, xe2x80x94CONHR8, xe2x80x94CONR8R8, xe2x80x94COOR8, xe2x80x94COR8, xe2x80x94OCOR8, xe2x80x94OR8, xe2x80x94BH2, xe2x80x94BHR8, xe2x80x94BR8R8, xe2x80x94BO2H2, xe2x80x94BO2R8R8, xe2x80x94PH2, xe2x80x94PHR8, xe2x80x94PR8R8, xe2x80x94POR8, xe2x80x94PO2R8, xe2x80x94PO3R8, xe2x80x94SR8; xe2x80x94SOR8, xe2x80x94SO2R8, xe2x80x94SONH2, xe2x80x94SONHR8, xe2x80x94SONR8R8, xe2x80x94SO2NH2, xe2x80x94SO2NHR8 and xe2x80x94SO2NR8R8;
R7 is a C1-C30 hydrocarbyl, halocarbyl or hydrohalocarbyl group wherein n of the hydrogen or halogen atoms of R7 are substituted by an equal number of W groups independently selected at each location;
R8 is a C1-C30 hydrocarbyl, halocarbyl or hydrohalocarbyl group;
n is selected from 0, 1, 2, 3, 4 and 5; and
X is selected from xe2x80x94Br, xe2x80x94Cl, xe2x80x94F, xe2x80x94I.
In one aspect, the compound of formula (4) has the S configuration at carbon 3. In another aspect, the compound of formula (4) has the R configuration at carbon 3. In another aspect, the compound of formula (4) has the S configuration at carbon 5. In another aspect, the compound of formula (4) has the R configuration at carbon 5. In another aspect, none of the carbons at positions 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, or 19 in formula (4) is substituted with a heterocyclic moiety.
In other aspects, in the compound of formula (4), as well as in compositions comprising the compound of formula (4) and a pharmaceutically acceptable carrier, diluent or excipient: Q is O; Q is S; Q is NH; and/or Q is N(R7(W)n). In other aspects, the carbon(s) at position 4, or 6, and preferably both of positions 4 and 6, are substituted exclusively with hydrogen; the carbon at position 19 is substituted with xe2x80x94W; the carbon at position 19 is substituted with xe2x80x94NH2, xe2x80x94NHR8, or xe2x80x94NR8R8; the carbon at position 19 is substituted with xe2x80x94CN, xe2x80x94X, xe2x80x94OH, xe2x80x94NO2, xe2x80x94SH, or xe2x80x94OR8; one carbon at positions 17 and 18 is substituted with hydrogen; at least one carbon at positions 17 and 18 is substituted with xe2x80x94W; at least one carbon at positions 17 and 18 is substituted with xe2x80x94NH2, xe2x80x94CONH2, xe2x80x94COOH, xe2x80x94CN, xe2x80x94CHO, xe2x80x94OCHO, xe2x80x94X, xe2x80x94OH, xe2x80x94NO2, xe2x80x94SH, xe2x80x94COX, xe2x80x94NHR8, xe2x80x94NR8R8, xe2x80x94CONHR8, xe2x80x94CONR8R8, xe2x80x94COOR8, xe2x80x94COR8, xe2x80x94OCOR8, or xe2x80x94R8; at least one carbon at positions 17 and 18 is substituted with xe2x80x94NH2, or xe2x80x94NR8R8; and/or at least one carbon at positions 17 and 18 is substituted with xe2x80x94CN, xe2x80x94X, xe2x80x94OH, xe2x80x94NO2, xe2x80x94SH, or xe2x80x94OR8. In another aspect, only one of the carbons at positions 17, 18 and 19 is substituted with hydrogen. In another aspect, exactly two of the carbons at positions 17, 18 and 19 are substituted with hydrogen. In another aspect, none of the carbons at positions 17, 18 and 19 are substituted with hydrogen. In another aspect, no more than one of the carbons at positions 17, 18 and 19 are substituted with hydrogen.
In other aspects, in the compound of formula (4), as well as in compositions comprising the compound of formula (4) and a pharmaceutically acceptable carrier, diluent or excipient: the carbon at position 7 is substituted exclusively with hydrogen; the carbon at position 3 is substituted with hydrogen; the carbon at position 3 is substituted with xe2x80x94W; the carbon at position 3 is substituted with halogen; the carbon at position 3 is substituted with xe2x80x94R7(W)n; the carbon at position 3 is substituted with C1-C6hydrocarbyl; the carbons at positions 9 and 10 are substituted with hydrogen; the carbons at positions 11, 12, and 13 are independently substituted with hydrogen and xe2x80x94W; only one of the carbons at positions 11 and 12 is substituted with hydrogen; the carbon at position 11 and/or 12 is substituted with xe2x80x94NH2, xe2x80x94CONH2, xe2x80x94COOH, xe2x80x94CN, xe2x80x94CHO, xe2x80x94OCHO, xe2x80x94X, xe2x80x94OH, xe2x80x94NO2, xe2x80x94SH, xe2x80x94COX, xe2x80x94NHR8, xe2x80x94NR8R8, xe2x80x94CONHR8, xe2x80x94CONR8R8, xe2x80x94COOR8, xe2x80x94COR8, xe2x80x94OCOR8, or xe2x80x94OR8; the carbon at position 11 and/or 12 is substituted with xe2x80x94NH2, xe2x80x94NHR8, or xe2x80x94NR8R8; the carbon at position 11 and/or 12 is substituted with xe2x80x94CN, xe2x80x94X, xe2x80x94OH, xe2x80x94NO2, xe2x80x94SH, or xe2x80x94OR8; the carbon at position 13 is substituted with xe2x80x94NH2, xe2x80x94CONH2, xe2x80x94COOH, xe2x80x94CN, xe2x80x94CHO, xe2x80x94OCHO, xe2x80x94X, xe2x80x94OH, xe2x80x94NO2, xe2x80x94SH, xe2x80x94COX, xe2x80x94NHR8, xe2x80x94NR8R8, xe2x80x94CONHR8, xe2x80x94CONR8R8, xe2x80x94COOR8, xe2x80x94COR8, xe2x80x94OCOR8, or xe2x80x94OR8; the carbon at position 13 is substituted with xe2x80x94NH2, xe2x80x94NHR8, or xe2x80x94NR8R8; the carbon at position 13 is substituted with xe2x80x94CN, xe2x80x94X, xe2x80x94OH, xe2x80x94NO2, xe2x80x94SH, or xe2x80x94OR8; at least one carbon from positions 11, 12, and 13 is substituted with xe2x80x94R7(W)n; and/or at least one carbon from positions 11, 12, and 13 is substituted with C1-C6hydrocarbyl or C1-C6halocarbyl or C1-C6hydrohalocarbyl.
In another aspect, only one of the carbons at positions 11, 12, and 13 is substituted with hydrogen. In another aspect, exactly two of the carbons at positions 11, 12, and 13 are substituted with hydrogen. In another aspect, none of the carbons at positions 11, 12, and 13 are substituted with hydrogen. In another aspect, no more than one of the carbons at positions 11, 12, and 13 are substituted with hydrogen.
In compounds of formula (4), and compositions comprising one or more compounds of formula (4) and a pharmaceutically acceptable carrier, diluent or excipient, the carbon at position 6 is preferably not substituted with either xe2x95x90O or xe2x95x90S; the carbon at position 4 is preferably not substituted with xe2x95x90O; the phenyl ring bonded to the carbon at position 5 is preferably substituted with no more than 4 hydrogen atoms; the phenyl ring bonded to the carbon at position 5 is preferably substituted with no more than 4 R7(W)n groups, and/or the compounds of formula (4) preferably exclude massonianalactone.
Thus, in a preferred compound of formula (4), Q is O or NH, the carbon at position 6 is substituted with not substituted with either xe2x95x90O or xe2x95x90S; the carbon at position 4 is not substituted with xe2x95x90O; the phenyl ring bonded directly to carbon 5 is directly substituted in at least one position with an atom other than carbon or hydrogen; and massonianalactone is excluded. Massonianalactone, which has the CAS Registry No. of 150270-05-6, is also known as 2H-pyran-2-one, tetrahydro-3-hydroxy-5-(4-hydroxy-3-methoxyphenyl)-3-[(4-hydroxy-3-methoxyphenyl)methyl]-, (3R-trans).
In a preferred embodiment, in compounds of formula (4), and compositions comprising a compound of formula (4), Q is NH, and not both of positions 17 and 18 are substituted with hydrogen.
The compounds disclosed herein of formulae 1, 2, 3 or 4 (i.e., compounds of formulae (1-4), or compounds of the present invention), or compositions comprising one of more of these compounds and a pharmaceutically acceptable carrier, diluent or excipient, may be used in a method for treating or preventing an inflammatory condition or disease in a patient, where the method comprises administering to the patient in need thereof an amount of a compound or composition according to the present invention, where the amount is effective to treat or prevent the inflammatory condition or disease of the patient.
The inflammatory condition or disease may be an autoimmune condition or disease; the inflammatory condition or disease may involve acute or chronic inflammation of bone and/or cartilage compartments of joints; the inflammatory condition or disease may be an arthritis selected from rheumatoid arthritis, gouty arthritis or juvenile rheumatoid arthritis; the inflammatory condition or disease may be asthma; the condition or disease may be associated with the disregulation of T-cells; the condition or disease may be associated with elevated levels of inflammatory cytokines (e.g., wherein the inflammatory cytokine is IL-2, or wherein the inflammatory cytokine is IFN-xcex3, or wherein the inflammatory cytokine is TNF-xcex1); the inflammatory condition or disease may be multiple sclerosis; the inflammatory condition or disease may be pulmonary sarcadosis; the inflammatory condition or disease may be ocular inflammation or allergy; the inflammatory condition or disease may be an inflammatory bowel disease (e.g., Crohn""s disease or ulcerative colitis); and the inflammatory condition or disease may be an inflammatory cutaneous disease (e.g., psoriasis or dermatitis).
Furthermore, the present invention provides a method for modulating intracellular cyclic adenosine 5xe2x80x2-monophosphate levels within a patient, comprising administering to a patient in need thereof an amount of a compound or composition according to the present invention, wherein the amount is effective to modulate the intracellular cyclic adenosine 5xe2x80x2-monophosphate levels of the patient. The patient may have an inflammatory condition or disease.
Furthermore, the present invention provides a method for treating or preventing a disease or condition in a patient, where the disease or condition is associated with pathological conditions that are modulated by inhibiting enzymes associated with secondary cellular messengers, the method comprising administering to a patient in need thereof an amount of a compound or a composition of the present invention, wherein the amount is effective to treat or prevent a disease or condition associated with pathological conditions that are modulated by inhibiting enzymes associated with secondary cellular messengers. The enzyme may be a cyclic AMP phosphodiesterase; or the enzyme may be a phosphodiesterase 4; or the enzyme may be a phosphodiesterase 3; or the enzymes may be both of phosphodiesterase 4 and phosphodiesterase 3; or the enzyme may be a cyclic GMP phosphodiesterase.
Furthermore, the present invention provides a method of treating or preventing transplant rejection in a patient, comprising administering to a patient in need thereof an amount of a compound or composition of the present invention, where the amount is effective to treat or prevent transplant rejection in the patient. The rejection may be due to graft versus host disease.
Furthermore, the present invention provides a method of treating or preventing uncontrolled cellular proliferation in a patient, comprising administering to a patient in need thereof an amount of a compound or composition according to the present invention, where the amount is effective to treat or prevent uncontrolled cellular proliferation in the patient. The uncontrolled cellular proliferation may be caused by a cancer selected from leukemia and solid tumors.
Furthermore, the present invention provides a method of treating or preventing conditions associated with the central nervous system (CNS) in a patient, comprising administering to a patient in need thereof an amount of a compound or composition according to the present invention, where the amount is effective to treat or prevent conditions associated with the central nervous system (CNS) in the patient. The condition associated with the central nervous system (CNS) may be depression.
In a method of the present invention, a compound of formulae (1-4), or a composition comprising one or more compounds of formulae (1-4) and a pharmaceutically acceptable carrier, diluent or excipient, may, although need not, achieve one or more of the following desired results in the subject to whom has been administered a compound of formulae (1-4) as defined above, or a composition containing one of these compounds and a pharmaceutically acceptable carrier, diluent or excipient:
1. Inhibition of reactive oxygen species generation from primary neutrophils;
2. Inhibition of neutrophil chemotaxis;
3. Inhibition of TNF-xcex1 production;
4. Inhibition of edema;
5. Oxygen radical scavenging;
6. Inhibition of cyclic-AMP phosphodiesterases 1, 3 and/or 4, and related PDEs such as PDE7;
7. Potentiate induction of CRE-mediated transcription activity in human monocytic cells;
8. Inhibition of PDE, preferably PDE4, PDE3, or PDE3 and PDE4;
9. Inhibition of cytokine production by activated T-cell subsets;
10. Inhibition of neutrophil myeloperoxidase release;
11. Low ratio of IC50 PDE4(cat):IC50PDE4(HARBS);
12. Inhibition of graft rejection;
13. Inhibition of clinical and histopathological parameters of disease in inflammatory bowel disease; and
14. Inhibition of clinical and histopathological parameters of arthritis in a murine collage-induced arthritis model.
These and other aspects and embodiments of the present invention will be apparent upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain procedures, compounds and/or compositions, and are hereby incorporated by reference in their entirety.
The present invention provides compounds, compositions and methods useful in the treatment and/or prevent of various disease conditions. For example, in one aspect, the present invention provides a method of treating and/or preventing an inflammatory disease. The method includes administering to a subject in need thereof a therapeutically-effective amount of a compound or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a composition containing a compound of formulae or a pharmaceutically acceptable salt thereof, of any of the compounds of formulae (1-4) as defined herein.
In one aspect, the present invention provides a composition comprising a compound according to formula (1) and salts, solvates, isolated stereoisomers, and mixtures thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, 
wherein each of hydrogens Ha, Hb, Hc, Hd, He, Hf and Hg may independently be replaced with a group selected from xe2x80x94W and xe2x80x94R7(W)n, and M1 represents xe2x80x94W or xe2x80x94R7(W)n, wherein
W is selected from xe2x80x94NH2, xe2x80x94CONH2, xe2x80x94COOH, xe2x80x94CN, xe2x80x94CHO, xe2x80x94OCHO, xe2x80x94X, xe2x80x94OH, xe2x80x94NO2, xe2x80x94SH, xe2x80x94COX, xe2x80x94NHR8, xe2x80x94N8R8, xe2x80x94CONHR8, xe2x80x94CONR8R8, xe2x80x94COOR8, xe2x80x94COR8, xe2x80x94OCOR8, xe2x80x94OR8, xe2x80x94BH2, xe2x80x94BHR8, xe2x80x94BR8R8, xe2x80x94BO2H2, xe2x80x94BO2R8R8, xe2x80x94PH2, xe2x80x94PHR8, xe2x80x94PR8R8, xe2x80x94POR8, xe2x80x94PO2R8, xe2x80x94PO3R8, xe2x80x94SR8; xe2x80x94SOR8, xe2x80x94SO2R8, xe2x80x94SONH2, xe2x80x94SONHR8, xe2x80x94SONR8R8, xe2x80x94SO2NH2, xe2x80x94SO2NHR8 and xe2x80x94SO2NR8R8;
R7 is a C1-C30 hydrocarbyl, halocarbyl or hydrohalocarbyl group wherein n of the hydrogen or halogen atoms of R7 are substituted by an equal number of W groups independently selected at each location;
R8 is a C1-C30 hydrocarbyl, halocarbyl or hydrohalocarbyl group;
n is selected from 0, 1, 2, 3, 4 and 5; and
X is selected from xe2x80x94Br, xe2x80x94Cl, xe2x80x94F, xe2x80x94I.
In other aspects of the composition comprising a compound of formula (1): Ha and Hb are hydrogen; Ha is hydrogen and Hb is xe2x80x94W; Ha is hydrogen, Hb is xe2x80x94W and the carbon to which Hb is bound has an S configuration; Ha is hydrogen, Hb is xe2x80x94W, and the carbon to which Hb is bound has an R configuration; Ha is hydrogen and Hb is xe2x80x94R7(W)n; Ha is hydrogen, Hb is xe2x80x94R7(W)n, and the carbon to which Hb is bound has an S configuration; Ha is hydrogen, Hb is xe2x80x94R7(W)n, and the carbon to which Hb is bound has an R configuration; Ha is hydrogen, Hb is xe2x80x94R7(W)n, Hb is xe2x80x94CH2-phenyl, and phenyl has 0, 1 or 2 W substitutions; Hc is W; Hd and He are both hydrogen; Hf is W; Hf is selected from xe2x80x94OH and xe2x80x94OR8; Hf is selected from methoxy, ethoxy, propoxy, cyclopentyloxy, cyclohexyloxy, and benzyloxy; Hf is selected from xe2x80x94NH2, xe2x80x94NHR8, and xe2x80x94NR8R8; Hg is xe2x80x94R7(W)n; M1 is xe2x80x94W; M1 is selected from methoxy, ethoxy, propoxy, cyclopentyloxy, cyclohexyloxy, and benzyloxy; M1 is selected from xe2x80x94NH2, xe2x80x94NHR8, and xe2x80x94NR8R8; M1 is selected from xe2x80x94OH and xe2x80x94OR8; and/or M1 is xe2x80x94R7(W)n. In one embodiment, none of Ha, Hb, Hc, Hd, He, Hf or Hg is a heterocyclic ring.
The compound of formula (1) may have the stereochemistry of formula (1a) 
The compound of formula (1) may have the stereochemistry of formula (1b) 
A reference herein to compounds of formula (1) includes compounds of formulae (1a) and (1b).
In another aspect, the present invention provides a composition comprising a compound according to formula (2) and salts, solvates, isolated stereoisomers, and mixtures thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, 
wherein each of hydrogens Ha, Hb, Hc, Hd, He, Hf and Hg may independently be replaced with a group selected from xe2x80x94W and R7(W)n, and M2 represents xe2x80x94W, wherein
W is selected from xe2x80x94NH2, xe2x80x94CONH2, xe2x80x94COOH, xe2x80x94CN, xe2x80x94CHO, xe2x80x94OCHO, xe2x80x94X, xe2x80x94OH, xe2x80x94NO2, xe2x80x94SH, xe2x80x94COX, xe2x80x94NHR8, xe2x80x94NR8R8, xe2x80x94CONHR8, xe2x80x94CONR8R8, xe2x80x94COOR8, xe2x80x94COR8, xe2x80x94OCOR8, OR8, xe2x80x94BH2, xe2x80x94BHR8, xe2x80x94BR8R8, xe2x80x94BO2H2, xe2x80x94BO2R8R8, xe2x80x94PH2, xe2x80x94PHR8, xe2x80x94PR8R8, xe2x80x94POR8, xe2x80x94PO2R8, xe2x80x94PO3R8, xe2x80x94SR8; xe2x80x94SOR8, xe2x80x94SO2R8, xe2x80x94SONH2, xe2x80x94SONHR8, xe2x80x94SONR8R8, xe2x80x94SO2NH2, xe2x80x94SO2NHR8 and xe2x80x94SO2NR8R8;
R7 is a C1-C30 hydrocarbyl, halocarbyl or hydrohalocarbyl group wherein n of the hydrogen or halogen atoms of R7 are substituted by an equal number of W groups independently selected at each location;
R8 is a C1-C30 hydrocarbyl, halocarbyl or hydrohalocarbyl group;
n is selected from 0, 1, 2, 3, 4and 5; and
X is selected from xe2x80x94Br, xe2x80x94Cl, xe2x80x94F, xe2x80x94I.
In other aspects of compositions comprising a compound of formula (2): Ha and Hb are hydrogen; Ha is hydrogen and Hb is xe2x80x94W; Ha is hydrogen, Hb is xe2x80x94W, and the carbon to which Hb is bound has an S configuration; Ha is hydrogen, Hb is xe2x80x94W, and the carbon to which Hb is bound has an R configuration; Ha is hydrogen and Hb is xe2x80x94R7(W)n; Ha is hydrogen, Hb is xe2x80x94R7(W)n, and the carbon to which Hb is bound has an S configuration; Ha is hydrogen, Hb is xe2x80x94R7(W)n, and the carbon to which Hb is bound has an r configuration; Ha is hydrogen, and Hb is xe2x80x94CH2-phenyl, where phenyl has 0, 1 or 2 W substitutions; H, is W; Hd and He are both hydrogen; Hf is hydrogen and Hg is W; Hg is selected from xe2x80x94OH and xe2x80x94OR8; Hg is selected from methoxy, ethoxy, propoxy, cyclopentyloxy, cyclohexyloxy, and benzyloxy; Hg is selected from xe2x80x94NH2, xe2x80x94NHR8, and xe2x80x94NR8R8; Hf is hydrogen and Hg is xe2x80x94R7(W)n; M2 is selected from xe2x80x94NH2, xe2x80x94CONH2, xe2x80x94COOH, xe2x80x94CN, xe2x80x94CHO, xe2x80x94OCHO, xe2x80x94X, xe2x80x94OH, xe2x80x94NO2, xe2x80x94SH, xe2x80x94COX, NHR8, xe2x80x94NR8R8, xe2x80x94CONHR8, xe2x80x94CONR8R8, xe2x80x94COOR8, xe2x80x94COR8, xe2x80x94OCOR8, and xe2x80x94OR8; and/or M2 is selected from xe2x80x94NH2, NHR8, xe2x80x94NR8R8, xe2x80x94OH, and xe2x80x94OR8. In a preferred embodiment, none of Ha, Hb, Hc, Hd, He, Hf or Hg may be replaced with a heterocyclic ring system.
The compound of formula (2) may have the stereochemistry of formula (2a) 
The compound of formula (2) may have the stereochemistry of formula (2b) 
A reference herein to compounds of formula (2) includes reference to compounds of formulae (2a) and (2b).
In another aspect, the present invention provides a compound according to formula (3) and salts, solvates, isolated stereoisomers, and mixtures thereof, 
wherein each of hydrogens Ha, Hc, Hd, He, Hf and Hg may independently be replaced with a group selected from xe2x80x94W and xe2x80x94R7(W)n, and Hb may be replaced with xe2x80x94W, wherein
W is selected from xe2x80x94NH2, xe2x80x94CONH2, xe2x80x94COOH, xe2x80x94CN, xe2x80x94CHO, xe2x80x94OCHO, xe2x80x94X, xe2x80x94OH, xe2x80x94NO2, xe2x80x94SH, xe2x80x94COX, xe2x80x94NHR8, xe2x80x94NR8R8, xe2x80x94CONHR8, xe2x80x94CONR8R8, xe2x80x94COOR8, xe2x80x94COR8, xe2x80x94OCOR8, xe2x80x94OR8, xe2x80x94BH2, xe2x80x94BHR8, xe2x80x94BR8R8, xe2x80x94BO2H2, xe2x80x94BO2R8R8, xe2x80x94PH2, xe2x80x94PHR8, xe2x80x94PR8R8, xe2x80x94POR8, xe2x80x94POR8, xe2x80x94PO3R8, xe2x80x94SR8; xe2x80x94SOR8, xe2x80x94SO2R8, xe2x80x94SONH2, xe2x80x94SONHR8, xe2x80x94SONR8R8, xe2x80x94SO2NH2, xe2x80x94SO2NHR8 and xe2x80x94SO2NR8R8;
R7 is a C1-C30 hydrocarbyl, halocarbyl or hydrohalocarbyl group wherein n of the hydrogen or halogen atoms of R7 are substituted by an equal number of W groups independently selected at each location;
R8 is a C1-C30 hydrocarbyl, halocarbyl or hydrohalocarbyl group;
n is selected from 0, 1, 2, 3, 4 and 5; and
X is selected from xe2x80x94Br, xe2x80x94Cl, xe2x80x94F, xe2x80x94I.
In a preferred embodiment, at least two of He, Hf, and Hg are not hydrogen. In another preferred embodiment, Hg is not R7(W)n. In another preferred embodiment, Hg is neither hydrogen nor R7(W)n. In another preferred embodiment, none of Ha, Hb, Hc, Hd, He, Hf or Hg is a heterocyclic ring.
In other aspects, in the compound of formula (3): Ha is hydrogen; Ha is not hydrogen, and the carbon to which Ha is bound has an S configuration; Ha is not hydrogen and the carbon to which Ha is bound has an R configuration; Ha is xe2x80x94W; Ha is xe2x80x94R7(W)n; Ha is xe2x80x94CH2-phenyl, and phenyl has 0, 1 or 2 W substitutions; Hb is W; Hb is xe2x80x94CN; Hc and Hd are both hydrogen; He is hydrogen; He is hydrogen and Hf is W; He is hydrogen and Hf is selected from xe2x80x94OH and xe2x80x94OR8; He is hydrogen and Hf is selected from methoxy, ethoxy, propoxy, cyclopentyloxy, cyclohexyloxy, and benzyloxy; He is hydrogen and Hf is selected from xe2x80x94NH2, xe2x80x94NHR8, and xe2x80x94NR8R8; Hg is hydrogen; Hg is xe2x80x94W; Hg is selected from xe2x80x94OH and xe2x80x94OR8; Hg is selected from methoxy, ethoxy, propoxy, cyclopentyloxy, cyclohexyloxy, and benzyloxy; wherein Hg is selected from xe2x80x94NH2, xe2x80x94NHR8, and xe2x80x94NR8R5; Hg is xe2x80x94R7(W)n; and/or Hg is C1-C30alkyl and n=0.
The compound of formula (3) may have the stereochemistry of formula (3) 
The compound of formula (3) may have the stereochemistry of formula (3b) 
A reference herein to compounds of formula (3) includes reference to compounds of formulae (3a) and (3b).
In another aspect, the present invention provides compounds of formula (4) 
wherein, Q represents a multivalent atom other than carbon; and
each of the carbons at positions 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, and 19 in formula (4), as well as Q to the extent that it may be substituted, is independently substituted at each occurrence with H, xe2x80x94W or xe2x80x94R7(W)n, wherein
W is selected from xe2x80x94NH2, xe2x80x94CONH2, xe2x80x94COOH, xe2x80x94CN, xe2x80x94CHO, xe2x80x94OCHO, xe2x80x94X, xe2x80x94OH, xe2x80x94NO2, xe2x80x94SH, xe2x80x94COX, xe2x80x94NR8, xe2x80x94NR8R8, xe2x80x94CONHR8, xe2x80x94CONR8R8, xe2x80x94COOR8, xe2x80x94COR8, xe2x80x94OCOR8, xe2x80x94OR8, xe2x80x94BH2, xe2x80x94BHR8, xe2x80x94BR8R8, xe2x80x94BO2H2, xe2x80x94BO2R8R8, xe2x80x94PH2, xe2x80x94PHR8, xe2x80x94PR8R8, xe2x80x94POR8, xe2x80x94PO2R8, xe2x80x94PO3R8, xe2x80x94SR8; xe2x80x94SOR8, xe2x80x94SO2R8, xe2x80x94SONH2, xe2x80x94SONHR8, xe2x80x94SONR8R8, xe2x80x94SO2NH2, xe2x80x94SO2NHR8 and xe2x80x94SO2NR8R8;
R7 is a C1-C30 hydrocarbyl, halocarbyl or hydrohalocarbyl group wherein n of the hydrogen or halogen atoms of R7 are substituted by an equal number of W groups independently selected at each location;
R8 is a C1-C30 hydrocarbyl, halocarbyl or hydrohalocarbyl group;
n is selected from 0, 1, 2, 3, 4 and 5; and
X is selected from xe2x80x94Br, xe2x80x94Cl, xe2x80x94F, xe2x80x94I.
In one aspect, the compound of formula (4) has the S configuration at carbon 3. In another aspect, the compound of formula (4) has the R configuration at carbon 3. In another aspect, the compound of formula (4) has the S configuration at carbon 5. In another aspect, the compound of formula (4) has the R configuration at carbon 5. In another aspect, none of the carbons at positions 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, or 19 in formula (4) is substituted with a heterocyclic moiety.
In other aspects, in the compound of formula (4), as well as in compositions comprising the compound of formula (4) and a pharmaceutically acceptable carrier, diluent or excipient: Q is O; Q is S; Q is NH; and/or Q is N(R7(W)n). In other aspects, the carbon(s) at position 4, or 6, and preferably both of positions 4 and 6, are substituted exclusively with hydrogen; the carbon at position 19 is substituted with xe2x80x94W; the carbon at position 19 is substituted with xe2x80x94NH2, xe2x80x94NHR8, or xe2x80x94NR8R8; the carbon at position 19 is substituted with xe2x80x94CN, xe2x80x94X, xe2x80x94OH, xe2x80x94NO2, xe2x80x94SH, or xe2x80x94OR8; one carbon at positions 17 and 18 is substituted with hydrogen; at least one carbon at positions 17 and 18 is substituted with xe2x80x94W; at least one carbon at positions 17 and 18 is substituted with xe2x80x94NH2, xe2x80x94CONH2, xe2x80x94COOH, xe2x80x94CN, xe2x80x94CHO, xe2x80x94OCHO, xe2x80x94X, xe2x80x94OH, xe2x80x94NO2, xe2x80x94SH, xe2x80x94COX, xe2x80x94NHR8, xe2x80x94NR8R8, xe2x80x94CONHR8, xe2x80x94CONR8R8, xe2x80x94COOR8, xe2x80x94COR8, xe2x80x94OCOR8, or xe2x80x94OR8; at least one carbon at positions 17 and 18 is substituted with xe2x80x94NH2, NHR8, or xe2x80x94NR8R8; and/or at least one carbon at positions 17 and 18 is substituted with xe2x80x94CN, xe2x80x94X, xe2x80x94OH, xe2x80x94NO2, xe2x80x94SH, or xe2x80x94OR8. In another aspect, only one of the carbons at positions 17, 18 and 19 is substituted with hydrogen. In another aspect, exactly two of the carbons at positions 17, 18 and 19 are substituted with hydrogen. In another aspect, none of the carbons at positions 17, 18 and 19 are substituted with hydrogen. In another aspect, no more than one of the carbons at positions 17, 18 and 19 are substituted with hydrogen.
In other aspects, in the compound of formula (4), as well as in compositions comprising the compound of formula (4) and a pharmaceutically acceptable carrier, diluent or excipient: the carbon at position 7 is substituted exclusively with hydrogen; the carbon at position 3 is substituted with hydrogen; the carbon at position 3 is substituted with xe2x80x94W; the carbon at position 3 is substituted with halogen; the carbon at position 3 is substituted with xe2x80x94R7(W)n; the carbon at position 3 is substituted with C1-C6hydrocarbyl; the carbons at positions 9 and 10 are substituted with hydrogen; the carbons at positions 11, 12, and 13 are independently substituted with hydrogen and xe2x80x94W; only one of the carbons at positions 11 and 12 is substituted with hydrogen; the carbon at position 11 and/or 12 is substituted with xe2x80x94NH2, xe2x80x94CONH2, xe2x80x94COOH, xe2x80x94CN, xe2x80x94CHO, xe2x80x94OCHO, xe2x80x94X, xe2x80x94OH, xe2x80x94NO2, xe2x80x94SH, xe2x80x94COX, xe2x80x94NHR8, xe2x80x94NR8R8, xe2x80x94CONHR8, xe2x80x94CONR8R8, xe2x80x94COOR8, xe2x80x94COR8, xe2x80x94OCOR8, or xe2x80x94OR8; the carbon at position 11 and/or 12 is substituted with xe2x80x94NH2, xe2x80x94NHR8, or xe2x80x94NR8R8; the carbon at position 11 and/or 12 is substituted with xe2x80x94CN, xe2x80x94X, xe2x80x94OH, xe2x80x94NO2, xe2x80x94SH, or xe2x80x94OR8; the carbon at position 13 is substituted with xe2x80x94NH2, xe2x80x94CONH2, xe2x80x94COOH, xe2x80x94CN, xe2x80x94CHO, xe2x80x94OCHO, xe2x80x94X, xe2x80x94OH, xe2x80x94NO2, xe2x80x94SH, xe2x80x94COX, xe2x80x94NHR8, xe2x80x94NR8R8, xe2x80x94CONHR8, xe2x80x94CONR8R8, xe2x80x94COOR8, xe2x80x94COR8, xe2x80x94OCOR8, or xe2x80x94OR8; the carbon at position 13 is substituted with xe2x80x94NH2, xe2x80x94NHR8, or xe2x80x94NR8R8; the carbon at position 13 is substituted with xe2x80x94CN, xe2x80x94X, xe2x80x94OH, xe2x80x94NO2, xe2x80x94SH, or xe2x80x94OR8; at least one carbon from positions 11, 12, and 13 is substituted with xe2x80x94R7(W)n;
In another aspect, only one of the carbons at positions 11, 12, and 13 is substituted with hydrogen. In another aspect, exactly two of the carbons at positions 11, 12, and 13 are substituted with hydrogen. In another aspect, none of the carbons at positions 11, 12, and 13 are substituted with hydrogen. In another aspect, no more than one of the carbons at positions 11, 12, and 13 are substituted with hydrogen.
In compounds of formula (4), and compositions comprising one or more compounds of formula (4) and a pharmaceutically acceptable carrier, diluent or excipient, the carbon at position 6 is preferably not substituted with either xe2x95x90O or xe2x95x90S; the carbon at position 4 is preferably not substituted with xe2x95x90O; the phenyl ring bonded to the carbon at position 5 is preferably substituted with no more than 4 hydrogen atoms; the phenyl ring bonded to the carbon at position 5 is preferably substituted with no more than 4 R7(W)n groups, and/or the compounds of formula (4) preferably exclude massonianalactone.
Thus, in a preferred compound of formula (4), Q is O or NH, the carbon at position 6 is not substituted with either xe2x95x90O or xe2x95x90S; the carbon at position 4 is not substituted with xe2x95x90O; the phenyl ring bonded directly to carbon 5 is directly substituted in at least one position with an atom other than carbon or hydrogen; and massonianalactone is excluded. Massonianalactone, which has the CAS Registry No. of 150270-05-6, is also known as 2H-pyran-2-one, tetrahydro-3-hydroxy-5-(4-hydroxy-3-methoxyphenyl)-3-[(4-hydroxy-3-methoxyphenyl)methyl]-, (3R-trans).
In compounds of formulae (1-4):
W is selected from xe2x80x94NH2, xe2x80x94CONH2, xe2x80x94COOH, xe2x80x94CN, xe2x80x94CHO, xe2x80x94OCHO, xe2x80x94X, xe2x80x94OH, xe2x80x94NO2, xe2x80x94SH, xe2x80x94COX, xe2x80x94NHR8, xe2x80x94NR8R8, xe2x80x94CONHR8, xe2x80x94CONR8R8, xe2x80x94COOR8, xe2x80x94COR8, xe2x80x94OCOR8, xe2x80x94OR8, xe2x80x94BH2, xe2x80x94BHR8, xe2x80x94BR8R8, xe2x80x94BO2H2, xe2x80x94BO2R8R8, xe2x80x94PH2, xe2x80x94PHR8, xe2x80x94PR8R8, xe2x80x94POR8, xe2x80x94PO2R8, xe2x80x94PO3R8, xe2x80x94SR8; xe2x80x94SOR8, xe2x80x94SO2R8, xe2x80x94SONH2, xe2x80x94SONHR8, xe2x80x94SONR8R8, xe2x80x94SO2NH2, xe2x80x94SO2NHR8 and xe2x80x94SO2NR8R8;
R7 is a C1-C30 hydrocarbyl, halocarbyl or hydrohalocarbyl group wherein n of the hydrogen or halogen atoms of R7 are substituted by an equal number of W groups independently selected at each location;
R8 is a C1-C30 hydrocarbyl, halocarbyl or hydrohalocarbyl group;
n is selected from 0, 1, 2, 3, 4 and 5; and
X is selected from xe2x80x94Br, xe2x80x94Cl, xe2x80x94F, xe2x80x94I.
In preferred embodiments: W is selected from xe2x80x94NH2, xe2x80x94NHR8, and xe2x80x94NR8R8; W is selected from xe2x80x94CONH2, xe2x80x94COOH, xe2x80x94CN, xe2x80x94CHO, xe2x80x94COX, xe2x80x94CONHR8, xe2x80x94CONR8R8, xe2x80x94COOR8, xe2x80x94COR8; W is selected from, xe2x80x94OCHO, xe2x80x94OH, xe2x80x94OCOR8, and xe2x80x94OR8; W is selected from xe2x80x94BH2, xe2x80x94BHR8, xe2x80x94BR8R8, xe2x80x94BO2H2, xe2x80x94BO2R8R8, xe2x80x94PH2, xe2x80x94PHR8, xe2x80x94PR8R8, xe2x80x94POR8, xe2x80x94PO2R8, xe2x80x94PO3R8, xe2x80x94SR8; xe2x80x94SOR8, xe2x80x94SO2R8, xe2x80x94SONH2, xe2x80x94SONHR8, xe2x80x94SONR8R8, xe2x80x94SO2NH2, xe2x80x94SO2NHR8 and xe2x80x94SO2NR8R8; W is selected from xe2x80x94NH2, xe2x80x94CN, xe2x80x94X, xe2x80x94OH, xe2x80x94NO2, xe2x80x94SH, xe2x80x94NHR8, xe2x80x94NR R8, xe2x80x94OR8, and xe2x80x94SR8; and W is xe2x80x94OR8.
In preferred embodiments: R7 is a C1-C30 hydrocarbyl group wherein n of the hydrogen or halogen atoms of R7 are substituted by an equal number of W groups independently selected at each location; R7 is a C1-C10 hydrocarbyl group wherein n of the hydrogen or halogen atoms of R7 are substituted by an equal number of W groups independently selected at each location; and/or R7 is selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, alkenyl-substituted aryl, aryl-substituted alkenyl, alkynyl-substituted aryl, aryl-substituted alkynyl, biaryl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkylcycloalkyl, alkenylcycloalkyl, alkynylcycloalkyl, aryl-substituted cycloalkyl, cycloalkyl-substituted aryl, aryl-substituted cycloalkenyl, cycloalkenyl-substituted aryl, aryl-fused cycloalkyl and polycycloalkyl.
In preferred embodiments: R8 is a C1-C30 hydrocarbyl group; R8 is a C1-C10 hydrocarbyl group; and/or R8 is selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, alkenyl-substituted aryl, aryl-substituted alkenyl, alkynyl-substituted aryl, aryl-substituted alkynyl, biaryl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkylcycloalkyl, alkenylcycloalkyl, alkynylcycloalkyl, aryl-substituted cycloalkyl, cycloalkyl-substituted aryl, aryl-substituted cycloalkenyl, cycloalkenyl-substituted aryl, aryl-fused cycloalkyl and polycycloalkyl.
In preferred embodiments: n is 0; n is 1; n is 2; n is 3; n is 4; n is 5; n is greater than 0; n is 1 or 2; and n is 1 or 2 or 3.
In preferred embodiments, none of Ha through Hg is a heterocyclic ring.
In the above compounds, a pharmaceutically acceptable salt includes acid addition salts and base addition salts.
Acid addition salts refer to those salts formed from compounds of formulae (1-4) and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfric acid, nitric acid, phosphoric acid and the like, and/or organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
Base addition salts include those salts derived from compounds of formulae (1-4) and inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Suitable salts include the ammonium, potassium, sodium, calcium and magnesium salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaines, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and the like.
In the above compounds and compositions, a hydrocarbyl group is formed exclusively from carbon and hydrogen, and includes, for example, any of alkyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, alkenyl-substituted aryl, aryl-substituted alkenyl, alkynyl-substituted aryl, aryl-substituted alkynyl, biaryl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkylcycloalkyl, alkenylcycloalkyl, alkynylcycloalkyl, aryl-substituted cycloalkyl, cycloalkyl-substituted aryl, aryl-substituted cycloalkenyl, cycloalkenyl-substituted aryl, aryl-fused cycloalkyl and polycycloalkyl. A halocarbyl group is formed exclusively from carbon and halogen, and includes the hydrocarbyl groups identified above wherein each hydrogen is replaced with a halogen selected from fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine. A hydrohalocarbyl group, which may also be referred to as a halohydrocarbyl group, is formed from exclusively from all of carbon, hydrogen and halogen, and includes the specific hydrocarbyl groups identified above wherein some, but not all, of the hydrogen atoms are replaced with halogen atoms selected from fluorine, chlorine, bromine and iodine, preferably fluorine and/or chlorine. Representative definitions of these hydrocarbyl groups (which may be substituted with halogen atoms to provide halocarbyl and hydrohalocarbyl derivatives thereof) are provided below.
xe2x80x9cAlkylxe2x80x9d refers to an acyclic chain of carbon atoms which may be branched or unbranched (linear). Methyl, ethyl, propyl (including n-propyl and iso-propyl) butyl (including n-butyl, iso-butyl, sec-butyl, and t-butyl), pentyl (including numerous isomers) and hexyl (including numerous isomers) are alkyl groups having 1 to 6 carbon atoms (commonly referred to as lower alkyl groups), and are exemplary of alkyl groups of the invention.
xe2x80x9cAlkenylxe2x80x9d refers to an unsaturated aliphatic group having at least one double bond.
xe2x80x9cAlkynylxe2x80x9d refers to an unsaturated hydrocarbon which may be either straight- or branched-chain and have one or more triple bonds. Preferred groups have no more than about 12 carbons atoms and may be ethyl, propynyl, 4-methylpentynl and so on, and structure isomers thereof.
xe2x80x9cAralkylxe2x80x9d refers to an alkyl group substituted by an aryl radical. For example, benzyl.
xe2x80x9cAralkynylxe2x80x9d refers to an alkynyl group substituted by an aryl ring. For example, ArCxe2x89xa1Cxe2x80x94, ArCH2CH2CH2Cxe2x89xa1Cxe2x80x94 and so on.
xe2x80x9cCyloalkylxe2x80x9d refers to a cyclic arrangement of carbon atoms, where cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are cycloalkyl groups of the invention having 3-6 carbon atoms. Additional groups within the scope of xe2x80x9ccycloalkylxe2x80x9d as defined herein are polycycloalkyl groups, defined below.
xe2x80x9cCycloalkenylxe2x80x9d refers to a cyclic alkenyl group. Suitable cycloalkenyl groups include, for example, cyclopentenyl and cyclohexenyl.
A polycycloalkyl group is an arrangement of carbon atoms wherein at least one carbon atom is a part of at least two separately identifiable rings. The polycycloalkyl group may contain bridging between two carbon atoms, where bicyclo[1.1.0]butyl, bicyclo[3.2.1]octyl, bicyclo[5,2.0]nonyl, tricycl[2.2.1.01]heptyl, norbomyl and pinanyl are representative examples. The polycycloalkyl group may contain one or more fused ring systems, where decalinyl (radical from decalin) and perhydroanthracenyl are representative examples. The polycycloalkyl group may contain a spiro union, in which a single atom is the only common member of two rings. Spiro[3.4]octyl, spiro[3.3]heptyl and spiro[4.5]decyl are representative examples.
xe2x80x9cHalogenxe2x80x9d refers to fluorine, chlorine, bromine and iodine.
As used herein, the following abbreviations have the indicated meanings:
When any variable occurs more than one time in any constituent or in compounds of formulae (1-4), its definition on each occurrence is independent of its definition at every other occurrence. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. The compounds useful in the methods and compositions of the present invention, as well as the compounds of the present invention, may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention. A racemate or racemic mixture does not imply a 50:50 mixture of stereoisomers.
In another embodiment, the present invention provides pharmaceutical compositions containing a compound of formulae (1-4) as set forth above, in combination with a pharmaceutically-acceptable carrier, diluent or excipient. These compositions may be used for the treatment inflammation or other conditions as disclosed herein. These compositions may also be formed into a medicament, which may used in the treatment of, for example, inflammation.
These compositions are useful as, for example, assay standards, convenient means of making bulk shipments, or pharmaceutical compositions. An assayable amount of a compound of the invention is an amount which is readily measurable by standard assay procedures and techniques as are well known and appreciated by those skilled in the art. Assayable amounts of a compound of the invention will generally vary from about 0.001 wt % to about 80 wt % of the entire weight of the composition. Inert carriers include any material which does not degrade or otherwise covalently react with a compound of formulae (1-4). Examples of suitable inert carriers are water; aqueous buffers, such as those which are generally useful in High Performance Liquid Chromatography (HPLC) analysis; organic solvents, such as acetonitrile, ethyl acetate, hexane and the like; and pharmaceutically acceptable carriers.
xe2x80x9cPharmaceutically acceptable carriersxe2x80x9d for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remingtons Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). For example, sterile saline and phosphate-buffered saline at physiological pH may be used. Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition. For example, sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid may be added as preservatives. Id. at 1449. In addition, antioxidants and suspending agents may be used. Id.
Thus, the present invention provides a pharmaceutical or veterinary composition (hereinafter, simply referred to as a pharmaceutical composition) containing a compound of formulae (1-4) as described above, in admixture with a pharmaceutically acceptable carrier. The invention further provides a composition, preferably a pharmaceutical composition, containing an effective amount of a compound of (1-4) as described above, in association with a pharmaceutically acceptable carrier.
The pharmaceutical compositions of the present invention may be in any form which allows for the composition to be administered to a patient. For example, the composition may be in the form of a solid, liquid or gas (aerosol). Typical routes of administration include, without limitation, oral, topical, parenteral, sublingual, rectal, vaginal, and intranasal. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrastemal injection or infusion techniques. Pharmaceutical composition of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that will be administered to a patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a compound of formulae (1-4) in aerosol form may hold a plurality of dosage units.
Materials used in preparing the pharmaceutical compositions should be pharmaceutically pure and non-toxic in the amounts used. It will be evident to those of ordinary skill in the art that the optimal dosage of the active ingredient(s) in the pharmaceutical composition will depend on a variety of factors. Relevant factors include, without limitation, the type of subject (e.g., human), the particular form of the active ingredient, the manner of administration and the composition employed.
In general, the pharmaceutical composition includes an (where xe2x80x9caxe2x80x9d, and xe2x80x9canxe2x80x9d refers here, and throughout this specification, as one or more) active compound of formulae (1-4) as described herein, in admixture with one or more carriers. The carrier(s) may be particulate, so that the compositions are, for example, in tablet or powder form. The carrier(s) may be liquid, with the compositions being, for example, an oral syrup or injectable liquid. In addition, the carrier(s) may be gaseous, so as to provide an aerosol composition useful in, e.g., inhalatory administration.
When intended for oral administration, the composition is preferably in either solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.
As a solid composition for oral administration, the composition may be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like form. Such a solid composition will typically contain one or more inert diluents or edible carriers. In addition, one or more of the following adjuvants may be present: binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin, a flavoring agent such as peppermint, methyl salicylate or orange flavoring, and a coloring agent.
When the composition is in the form of a capsule, e.g., a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol, cyclodextrin or a fatty oil.
The composition may be in the form of a liquid, e.g., an elixir, syrup, solution, emulsion or suspension. The liquid may be for oral administration or for delivery by injection, as two examples. When intended for oral administration, preferred composition contain, in addition to the present compounds, one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer. In a composition intended to be administered by injection, one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included.
The liquid pharmaceutical compositions of the invention, whether they be solutions, suspensions or other like form, may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer""s solution, isotonic sodium chloride, fixed oils such as synthetic mono or digylcerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, cyclodextrin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. An injectable pharmaceutical composition is preferably sterile.
A liquid composition intended for either parenteral or oral administration should contain an amount of a compound of formulae (1-4) such that a suitable dosage will be obtained. Typically, this amount is at least 0.01% of a compound of the invention in the composition. When intended for oral administration, this amount may be varied to be between 0.1% and about 70% of the weight of the composition. Preferred oral compositions contain between about 4% and about 50% of the active compound of formulae (1-4). Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.01% to 1% by weight of active compound.
The pharmaceutical composition may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickening agents may be present in a pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device. Topical formulations may contain a concentration of the compound of formulae (1-4) of from about 0.1% to about 10% w/v (weight per unit 10 volume).
The composition may be intended for rectal administration, in the form, e.g., of a suppository which will melt in the rectum and release the drug. The composition for rectal administration may contain an oleaginous base as a suitable nonirritating excipient. Such bases include, without limitation, lanolin, cocoa butter and polyethylene glycol.
The composition may include various materials which modify the physical form of a solid or liquid dosage unit. For example, the composition may include materials that form a coating shell around the active ingredients. The materials which form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredients may be encased in a gelatin capsule.
The composition in solid or liquid form may include an agent which binds to the active component(s) and thereby assists in the delivery of the active components. Suitable agents which may act in this capacity include a monoclonal or polyclonal antibody, a protein or a liposome.
The pharmaceutical composition of the present invention may consist of gaseous dosage units, e.g., it may be in the form of an aerosol. The term aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system which dispenses the active ingredients. Aerosols of compounds of the invention may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient(s). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, spacers and the like, which together may form a kit. Preferred aerosols may be determined by one skilled in the art, without undue experimentation.
Whether in solid, liquid or gaseous form, the pharmaceutical composition of the present invention may contain one or more known pharmacological agents used in the treatment of inflammation (including arthritis).
The pharmaceutical compositions may be prepared by methodology well known in the pharmaceutical art.
A composition intended to be administered by injection can be prepared by combining the compound of formulae (1-4) with water so as to form a solution. A surfactant may be added to facilitate the formation of a homogeneous solution or suspension. Surfactants are compounds that non-covalently interact with the compound of formulae (1-4) so as to facilitate dissolution or homogeneous suspension of the active compound in the aqueous delivery system.
The compounds disclosed herein of formulae 1, 2, 3 or 4 (i.e., compounds of formulae (1-4), or compounds of the present invention), or compositions comprising one of more of these compounds and a pharmaceutically acceptable carrier, diluent or excipient, may be used in a method for treating or preventing an inflammatory condition or disease in a patient, where the method comprises administering to the patient in need thereof an amount of a compound or composition according to the present invention, where the amount is effective to treat or prevent the inflammatory condition or disease of the patient.
The inflammatory condition or disease may be an autoimmune condition or disease; the inflammatory condition or disease may involve acute or chronic inflammation of bone and/or cartilage compartments of joints; the inflammatory condition or disease may be an arthritis selected from rheumatoid arthritis, gouty arthritis or juvenile rheumatoid arthritis; the inflammatory condition or disease may be asthma; the condition or disease may be associated with the disregulation of T-cells; the condition or disease may be associated with elevated levels of inflammatory cytokines (e.g., wherein the inflammatory cytokine is IL-2, or wherein the inflammatory cytokine is IFN-xcex3, or wherein the inflammatory cytokine is TNF-xcex1); the inflammatory condition or disease may be multiple sclerosis; the inflammatory condition or disease may be pulmonary sarcadosis.; the inflammatory condition or disease may be ocular inflammation or allergy; the inflammatory condition or disease may be an inflammatory bowel disease (e.g., Crohn""s disease or ulcerative colitis); and the inflammatory condition or disease may be an inflammatory cutaneous disease (e.g., psoriasis or dermatitis).
Furthermore, the present invention provides a method for modulating intracellular cyclic adenosine 5xe2x80x2-monophosphate levels within a patient, comprising administering to a patient in need thereof an amount of a compound or composition according to the present invention, wherein the amount is effective to modulate the intracellular cyclic adenosine 5xe2x80x2-monophosphate levels of the patient. The patient may have an inflammatory condition or disease.
Furthermore, the present invention provides a method for treating or preventing a disease or condition in a patient, where the disease or condition is associated with pathological conditions that are modulated by inhibiting enzymes associated with secondary cellular messengers, the method comprising administering to a patient in need thereof an amount of a compound or a composition of the present invention, wherein the amount is effective to treat or prevent a disease or condition associated with pathological conditions that are modulated by inhibiting enzymes associated with secondary cellular messengers. The enzyme may be a cyclic AMP phosphodiesterase; or the enzyme may be a phosphodiesterase 4; or the enzyme may be a phosphodiesterase 3; or the enzymes may be both of phosphodiesterase 4 and phosphodiesterase 3; or the enzyme may be a cyclic GMP phosphodiesterase.
Furthermore, the present invention provides a method of treating or preventing transplant rejection in a patient, comprising administering to a patient in need thereof an amount of a compound or composition of the present invention, where the amount is effective to treat or prevent transplant rejection in the patient. The ejection may be due to graft versus host disease.
Furthermore, the present invention provides a method of treating or preventing uncontrolled cellular proliferation in a patient, comprising administering to a patient in need thereof an amount of a compound or composition according to the present invention, where the amount is effective to treat or prevent uncontrolled cellular proliferation in the patient. The uncontrolled cellular proliferation may be caused by a cancer selected from leukemia and solid tumors.
Furthermore, the present invention provides a method of treating or preventing conditions associated with the central nervous system (CNS) in a patient, comprising administering to a patient in need thereof an amount of a compound or composition according to the present invention, where the amount is effective to treat or prevent conditions associated with the central nervous system (CNS) in the patient. The condition associated with the central nervous system (CNS) may be depression.
In a method of the present invention, a compound of formulae (1-4), or a composition comprising one or more compounds of formulae (1-4) and a pharmaceutically acceptable carrier, diluent or excipient, may, although need not, achieve one or more of the following desired results in the subject to whom has been administered a compound of formulae (1-4) as defined above, or a composition containing one of these compounds and a pharmaceutically acceptable carrier, diluent or excipient:
1. Inhibition of reactive oxygen species generation from primary neutrophils;
2. Inhibition of neutrophil chemotaxis;
3. Inhibition of TNF-xcex1 production;
4. Inhibition of edema;
5. Oxygen radical scavenging;
6. Inhibition of cyclic-AMP phosphodiesterases 1, 3 and/or 4, and related PDEs such as PDE7;
7. Potentiate induction of CRE-mediated transcription activity in human monocytic cells;
8. Inhibition of PDE, preferably PDE4, PDE3, or PDE3 and PDE4;
9. Inhibition of cytokine production by activated T-cell subsets;
10. Inhibition of neutrophil myeloperoxidase release;
11. Low ratio of IC50 PDE4(cat):IC50PDE4(HARBS);
12. Inhibition of graft rejection;
13. Inhibition of clinical and histopathological parameters of disease in inflammatory bowel disease; and
14. Inhibition of clinical and histopathological parameters of arthritis in a murine collage-induced arthritis model.
Thus, the inventive method may be used to treat inflammation, including both acute and chronic inflammation as well as certain proliferative disorders (cancers). As used herein, inflammation includes, without limitation, ankylosing spondylitis, arthritis (where this term encompasses over 100 kinds of rheumatic diseases), asthma, Crohm""s disease, fibromyalgia syndrome, gout, inflammations of the brain (including multiple sclerosis, AIDS dementia, Lyme encephalopathy, herpes encephalitis, Creutzfeld-Jakob disease, and cerebral toxoplasmosis), emphysema, inflammatory bowel disease, irritable bowel syndrome, ischemia-reperfusion injury juvenile erythematosus pulmonary sarcoidosis, Kawasaki disease, osteoarthritis, pelvic inflammatory disease, psoriatic arthritis (psoriasis), rheumatoid arthritis, psoriasis, tissue/organ transplant, scleroderma, spondyloarthropathies, systemic lupus erythematosus, pulmonary sarcoidosis, and ulcerative colitis. As used herein, proliferative disorders includes, without limitation, all leukemias and solid tumors that are susceptible to undergoing differentiation or apoptosis upon interruption of their cell cycle.
The inventive method provides for administering a therapeutically effective amount of a compound of formulae (1-4), including salts, compositions etc. thereof. As used herein, the actual amount encompassed by the term xe2x80x9ctherapeutically effective amountxe2x80x9d will depend on the route of administration, the type of warm-blooded animal being treated, and the physical characteristics of the specific warm-blooded animal under consideration. These factors and their relationship to determining this amount are well known to skilled practitioners in the medical arts. This amount and the method of administration can be tailored to achieve optimal efficacy but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
An effective amount of a compound or composition of the present invention will be sufficient to treat inflammation in a warm-blooded animal, such as a human. Methods of administering effective amounts of anti-inflammatory agents are well known in the art and include the administration of inhalation, oral or parenteral forms. Such dosage forms include, but are not limited to, parenteral solutions, tablets, capsules, sustained release implants and transdermal delivery systems; or inhalation dosage systems employing dry powder inhalers or pressurized multi-dose inhalation devices.
The dosage amount and frequency are selected to create an effective level of the agent without harmful effects. It will generally range from a dosage of about 0.01 to 100 mg/Kg/day, and typically from about 0.1 to 10 mg/Kg/day where administered orally or intravenously. Also, the dosage range will be typically from about 0.01 to 1 mg/Kg/day where administered intranasally or by inhalation.
The compounds of formulae (1-4) including the compounds used in the methods and compositions set forth above, may be prepared according to the Schemes set forth in the following examples. The following examples are offered by way of illustration and not by way of limitation.
Unless otherwise stated, flash chromatography and column chromatography may be accomplished using Merck silica gel 60 (230-400 mesh). Flash chromatography may be carried out according to the procedure set forth in: xe2x80x9cPurification of Laboratory Chemicalsxe2x80x9d, 3rd. edition, Butterworth-Heinemann Ltd., Oxford (1988), Eds. D. D. Perrin and W. L. F. Armarego, page 23. Column chromatography refers to the process whereby the flow rate of eluent through a packing material is determined by gravity. In all cases flash chromatography and radial chromatography may be used interchangeably. Radial chromatography is performed using silica gel on a Chromatotron Model #7924T (Harrison Research, Palo Alto, Calif.). Unless otherwise stated, quoted Rf values are obtained by thin layer chromatography using Silica Gel 60 F254 (Merck KGaA, 64271, Darmstadt, Germany).
Also, unless otherwise stated, chemical reactants and reagents were obtained from standard chemical supply houses, such as Aldrich (Milwaukee, Wis.; www.aldrich.sial.com); EM Industries, Inc. (Hawthorne, N.Y.; www.emscience.com); Fisher Scientific Co. (Hampton, N.H.; www.fischer1.com); and Lancaster Synthesis, Inc. (Windham, N.H.; www.lancaster.co.uk). Gases were obtained from Praxair (Vancouver, B.C.). Cell lines, unless otherwise stated, where obtained from public or commercial sources, e.g., American Tissue Culture Collection (ATCC, Rockville, Md.).